PROJECT SUMMARY Tuberculosis (TB) is a re-emerging disease that is highly prevalent in the developing world, especially sub-Saharan Africa. However, despite the fact that a third of humans are exposed to Myocbacterium tuberculosis (MTB) complex bacteria, most immunocompetent individuals do not progress to active TB, but remain with asymptomatic latent TB infections (LTBI). In contrast, in immunocompromised individuals with LTBI, such as those infected with the human immunodeficiency virus (HIV+), the risk of active disease is 10% and more per year, making TB the most common cause of death for HIV+ individuals living in TB endemic countries. Nonetheless, many HIV+ individuals do not progress to active disease, exhibiting a resistance phenotype. We hypothesize that HIV+ individuals exposed to MTB, but who remain disease free for several years carry genomic and/or epigenomic variants that strongly protect them from active TB. To test this we will assay patterns of genetic and epigenetic variation in two prospective African cohorts, Kampala, Uganda and Dar es Salaam, Tanzania, where HIV+ patients have been followed for over a decade. We will compare the distribution of variants in people with active TB to those who have been exposed but do not develop disease. A third cohort from the high incidence HIV regions of Botswana will also be studied using the same platforms, high density GWAS and methylome chips, and ATAC-sequencing, to assess association with TB. We will use identify candidate genes for deep re-sequencing in selected individuals with the intent of identifying functional variants. Pathways that are found to protect from active disease in highly susceptible HIV+ individuals should provide novel targets for both treatment and means to prevent disease. Lastly, we will conduct immunological experiments to examine how these genetic variants affect the immune response to TB. The knowledge gained from this study design will be important in creating TB control regimens not only in Africa, but worldwide, as it will elucidate targets of unusually large effect that have not been investigated so far.